Mercury compounds of para-amino salicylic acid derivatives and a process of preparingthem



MERCURY. COMPOUNDS or PARA-AMINO SALI- CYLIC ACID DERIVATIVES AND APROCESS OF PREPARING THEM r No Drawing. Application September 22, 1952,

Serial No. 310,936' f Claims priority, application Germany September 26,1951 10 Claims. (Cl. 260-434) 'This invention relates to mercurycompounds of paraamino salicylic acid derivatives and aproce'ss .ofprepar ing them.

In modern pharmacy diuretics .play an important role. In most casesmercurial preparations are used, especially the derivatives of salicylicacid, for instance the complex mercury salicyl-allylamido-O-acetatesodium salt hasv gained considerable importance in therapy.

We have found that highly effective and essentially less toxicpreparations than the above-mentioned compounds of mercury-salicylicacid can be obtained by reacting esters of para-amino-salicylic acid,acylated in the amino group by a lower aliphatic carboxylic acidradical, with allylamine, condensing theallylamides thus obtained-in analkaline medium with lower aliphatic halocarboxylic acids and reactingthe condensation products with mercury salts of organic acids in thepersence of water or aliphatic monoor polyhydric alcohols.

The compounds produced according to this invention correspond to thefollowing general formula (CH2) 0 OOH in which R stands for hydrogen ora lower alkyl or lower dissolve more readily in water.

As esters of para-amino-salicylic acid, the esters with aromaticalcohols or phenols can also be used besides those with aliphaticalcohols. It is, however, preferable to use the esterswith aliphaticalcohols, especially low aliphatic alcohols such as methanol, ethanol,propanol,

isopropanol, butanol or amyl alcohol.

As halocarboxylic acids there may in the first place be mentioned, forinstance, aliphatic halocarboxylic acids. In particular it may beadvantageous to use low aliphatic halocarboxylic acids such aschloracetic acid, bromacetic acid or iodoacetic acid, chloropropionicacid, bromopropionic acid or iodopropionic acid, chlorobutyric acid,bromobutyric acid or iodobutyric acid.

As alcohols used as solvents in mercurization, monohydric and polyhydricalcohols may be used, for instance methanol, ethanol, propanol,isopropanol, butanol, amyl alcohol, ethylene glycol, 1.3-propyleneglycol, 1.2-propylene glycol, 1.4-butanediol, glycerol and the like.Especially advantageous is the use of polyhydric low aliphatic alcohols,because, by their use, the compatibility of the compounds and theirsolubility in water are remarkably increased.

The substances obtained are white, crystalline compounds. 8 The alkalisalts dissolve in water with a feebly alkaline 2,695,305 Patented Nov.23, 1954 reaction. The solutions may be bufiered, for instance "ice withtheocine. E: The compounds obtained according to the process'ofparatibility and increased solubility in water.

The following examples serve to illustrate the invention but they arenot intended to limit thereto:

j Example 1 17 grams of 4-acetylamino-2-hydroxy-benzoic acidmethylesterare heated to C. for 7 hours in a bomb tube with 11 cc. of allylamine.The contents of'the tube are taken up with acetone, the solvent and anyexcess of allylamine are distilled otf and the residue is recrystallizedfrom acetone. The 4-acetyl-amino-2-hydroxy-benzallylamide thus obtainedmelts at 218 C. (uncorrected).

14.05 grams of this product are dissolved in 80 cc. of water with 7 cc.of sodium hydroxide solution of 33 per cent. strength. To the solutionproduced 12.4 grams of chloracetic acid and 11 cc. of sodium hydroxidesolution of 33 per cent. strength are added in portions at 5 C. in sucha manner that the solution continuously remains alkaline tophenolphthalein. Finally, a further 5 cc. of sodium hydroxide solutionof 33 per cent. strength are added, the pH value thereby rising to 12.5.The mixture is heated on the water bath for 2 hours whereby the pH fallsto the neutral point and the reaction product partially precipitates.The mixture is diluted with water and by acidifying it with concentratedhydrochloric acid,

the 4 acetylamino 1 (N allylcarbamido) phenoxyacetic acid-2 is obtainedas a crude product. It is recrystallized from methanol and melts at 231"C. Into a solution of 8.35 grams of this product in cc. of absolutemethanol is run a solution of 7.7 grams of mercuric acetate in cc. ofabsolute methanol and the reaction mixture is heated under reflux for 1hour. The mercury addition product precipitates immediately, it is wellwashed with absolute methanol and ether and dried. The4-acetylamino-1-[N (3 hydroxy-mercuric-2'-methoxy-propyl-( l))-carbamido]-phenoxyactic acid-(2) melts at C. with decomposition. Inorder to convert {he free acid into the sodium salt, one proceeds asfolows:

12.25 grams of the mercury addition product are suspended in 18' cc. ofabsolute methanol and a sodium methylate solution'of 0.55 gram of sodiumand 15 cc. of methanol is slowly added drop by drop. The addition product gradually dissolves. The solution is passed through a close filterand the sodium salt is precipitated from the clear filtrate with amixture of 320 cc. of ether and 90 cc. of ethanol. The solution isfiltered oif with suction and well washed with ether and dried.

A white, crystalline powder is obtained, which, when exposed to air fora prolonged time is hygroscopic. The aqueous solution reacts feeblyalkaline and can be buffered with theocine.

Example 2 A hot solution of 31.8 grams of mercuric acetate in 500 cc. ofwater is added to a solution of 29.2 grams of 4- acetylamino -1- (Nallylcarbamido)-phenoxyacetic acid (2) in 3.5 litres of water. Themercury addition product precipitates immediately. The precipitate isfiltered off with suction, dissolved in sodium carbonate solution, thesolution is filtered and the filtrate is acidified with glacial aceticacid. The 4-acetylamino-1-[N-(3'-hydroxy-mercuric 2-hydroxy propyl-(l'))-carbamido]-2-phenoxyacetic acid separates in pure form and melts at203 C. with decomposition; the yield amounts to 41.2 grams. The sodiumsalt of the phenoxy-acetic acid thus obtained i; easily water-soluble;the solution can be bufiered with t eocine.

Example 3 After being allowed to stand for one day it is filtered ofi,

. well washedmithwater. .andiwhilemoist, dissolredagai in sodiumcarbonate solution. The solution is treated with carbon, filtered andacidified with glacial acetic 179 11 Caw thd qmim fim; wi t i b inobtained i s'j'water-s oluble; the solution can be buffered .withtheocine.

we'cla imr 1. Compounds of the general formula:

OR -Hg0H .0 G. 0 in which R stands for a member selected from the groupconsisting of hydrogen, lower alkyl and lower hydroiryalkyl radicals, R1represents a lower'aliph'at'ic acyl radical and n is a number from-'1 to3. 2. 'The compound of the formula:

l OCH: HgOH .(LQBLQQOH 3. .The compound ofthe formula:

011' gOH poonrooon Car carboxylic acid .4. A The compound of ..th ...tq.tnu a l O HgOH come 0 OH I CH2OH 5. The compound of the formula:

6. A process for the preparation of mercury compounds of para-aminosalicylic acid derivatives, wherein a p-amino-salicylie acid ester,acylated in the amino group by a lower aliphatic carboxylic acid'radicaL'i's reacted with allylamine, the allylamide thus obtained iscondensed, in an alkaline medium, with a lower aliphatic halop and thecondensation product is reacted with a mercury salt of anoi g'anie' acidin the presence of a liquids'elected from the group consisting of yvaterand lower aliphatic alcohols. H

7. A' processas clainlid'in clairn.6, wherein there is used as liquid 3*lower aliphatic" 'polyhydric alcohol.

"8.,A process for the preparation of ,mercu ryfiompounds ofpara-amino-salicylic' acid derivatives, wherein a p-ace tylaminosalicylic acid. ester isfreacted with ethylamine, the allylainide thusobtained is condensed, in an k l m w sh p es s' i an lth mndensationproduct is reacted with mercury acetate in the presence of a polyhydricalcohol.

9. A process as claimed in claim 8, whereind-lpropylene glycoljis usedas polyhydric alcohol.

10. A process as claimed in claim 8, wherein eth l ne glycol is usedaspolyhydric alcohol.

References .Qited in the f le of this patent UNITED STATES PATENTSNumber

1. COMPOUNDS OF THE GENERAL FORMULA: